Inhibitor for restenosis after percutaneous coronary arterioplasty

ABSTRACT

An inhibitor for restenosis after percutaneous coronary arterioplasty, which comprises, as an active ingredient, a compound of the following formula (1), (1&#39;) or a pharmaceutically acceptable salt thereof: ##STR1## wherein R 1  and R 2  are independently a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group, a C1-C6 alkyl group or a C1-C6 alkoxyl group, and R 1  and R 2  may be linked to form a methylenedioxy group; R 3  is an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, an optionally substituted 5 to 7-membered cycloalkyl or cycloalkenyl group; R 4  is a hydrogen atom, a hydroxyl group, an -S-glutathione residue, an -S-α-amino acid residue, or an aralkyl group optionally having substituent(s) in the aryl moiety; R 5  is a hydrogen atom or a C1-C6 alkyl group, and R 4  and R 5  may be linked to form a single bond; Y is an oxygen atom or a sulfur atom; n is an integer of from 0 to 5, and the selenium atom may be oxidized. 
     The inhibitor of the present invention exhibits excellent inhibitory effect against restenosis after PTCA with low toxicity.

This application is a 371 of PCT/JP93100045 Jan. 14, 1993

TECHNICAL FIELD

The present invention relates to a pharmaceutical agent for inhibitingrestenosis after percutaneous coronary arterioplasty (hereinafterreferred to as PTCA).

BACKGROUND ART

PTCA is a relatively new approach to the treatment of ischemic heartdiseases, which involves mechanical dilatation of the stenosed region ofthe coronary artery by balloons. However, the mechanically dilated partof the coronary arteries is known to undergo restenosis in severalmonths after operation with a frequency of about 40%. Thus, PTCA is nota radical therapy for stenosed lesions of the coronary arteries. Inorder to inhibit the restenosis, antiplatelets, anticoagulants, etc.have heretofore been studied, but drugs which provide satisfactoryclinical results have never been discovered.

Accordingly, there remains a need for a pharmaceutical agent whichexhibits excellent inhibiting effect against restenosis after PTCA.

Compounds of the following formula (1) or (1') are known to be useful asantioxidants having glutathione peroxidase-like activity and/orlipoxigenase inhibitory activity (see, for example, Japanese PatentApplication Laid-open Nos. 59-42373, 57-67568, 59-39894, 60-226868 and61-50963, Biochemical Pharmacology, vol. 33, No. 20, 3235 to 3239 and3241 to 3245 (1984)). However, the interrelation between theseactivities and the effect of inhibiting post-PTCA restenosis hasremained unknown.

In view of the above, the inventors of the present invention haveconducted careful studies and, as a result, have found that thecompounds of the following formula (1) or (1') have an excellent effectof inhibiting restenosis after PTCA. The present invention has beenaccomplished based on this finding.

DISCLOSURE OF INVENTION

According to the present invention, there is provided an inhibitor forrestenosis after percutaneous coronary arterioplasty, which comprises acompound of the following formula (1) or (1'), or a pharmaceuticallyacceptable salt thereof as an active ingredient: ##STR2## wherein R¹ andR² are independently a hydrogen atom, a halogen atom, a trifluoromethylgroup, a nitro group, a C1-C6 alkyl group or a C1-C6 alkoxyl group, andR¹ and R² may be linked to form a methylenedioxy group; R³ is anoptionally substituted aryl group, an optionally substituted aromaticheterocyclic group, an optionally substituted 5 to 7-membered cycloalkylor cycloalkenyl group; R⁴ is a hydrogen atom, a hydroxyl group, an-S-glutathione residue, an -S-α-amino acid residue, or an aralkyl groupoptionally having substituent(s) in the aryl moiety; R⁵ is a hydrogenatom or a C1-C6 alkyl group, and R⁴ and R⁵ may be linked to form asingle bond; Y is an oxygen atom or a sulfur atom; n is an integer offrom 0 to 5, and the selenium atom may be oxidized.

Inhibitors for restenosis according to the present invention exhibitexcellent effect of inhibiting restenosis after PTCA with low toxicity.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds which are used as active ingredients of inhibitors forrestenosis after PTCA according to the present invention are representedby the above-mentioned formula (1) or (1') (hereinafter referred to ascompound (1) or (1')). In the formulae, examples of C1-C6 alkyl groupsof R¹ include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl and pentyl; examples of C1-C6 alkoxyl groups of R¹ includemethoxy, ethoxy and propoxy; examples of aryl groups of R³ includephenyl; examples of cycloalkyl groups of R³ include cyclopentyl,cyclohexyl and cycloheptyl; examples of cycloalkenyl groups of R³include 1-cyclopentenyl, 1-cyclohexenyl and 1-cycloheptenyl; examples ofaromatic heterocyclic groups include 5- or 6-membered aromaticheterocyclic groups such as pyridyl, pyrimidyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, furyl, etc. These groups may optionally havesubstituent(s). Examples of the substituents include a C1-C6 alkylgroup, C1-C6 alkoxy group, a halogen atom, a carboxyl group and ahydroxyl group. The number of the substituent(s) is preferably from 1 to3. Among the mentioned various R⁴ groups, the -S-glutathione residue isa residue which is formed as a result of elimination of a hydrogen atomfrom the thiol moiety of glutathione; the -S-α-amino acid residue is aresidue which is formed as a result of elimination of a hydrogen atomfrom the thiol moiety of α-amino acid having a thiol group in themolecule, and examples of the aralkyl group include benzyl. Of these,compounds having R⁴ and R⁵ which are linked to form a single bond arepreferred, and in particular, 2-phenyl-1,2-benzoisoselenazol-3(2H)-onerepresented by the following formula is particularly preferred: ##STR3##

Compounds shown below which are considered to be active metabolites ofthe above compounds are also useful and encompassed by the presentinvention. ##STR4## wherein -S-G represents an -S-glutathione group,##STR5##

In the present invention, pharmaceutically acceptable salts of theabove-described compounds may also be used.

The compounds (1) and (1') are known compounds, and they can beprepared, for example, by methods described in the above-mentionedreferences.

The compounds (1) and (1'), and their pharmaceutically acceptable saltsdemonstrated excellent inhibitory effect on the restenosis after PTCA,as will be demonstrated in the test example described below. Regardingthe toxicity, the compounds were orally or intraperitoneallyadministered to mice and rats, and as a result, the compounds were foundto have an extremely low toxicity as evidenced by the LD₅₀ (mg/kg)values in the following table. High doses of the compounds did not causeany adverse side effects.

                  TABLE 1                                                         ______________________________________                                        Animals tested                                                                            Administration Route                                                                         LD.sub.50 (mg/kg)                                  ______________________________________                                        Mice        p.o.           >6810                                                          i.p.             740                                              Rats        p.o.           >6810                                                          i.p.             580                                              ______________________________________                                    

The restenosis inhibitors of the present invention can be prepared byany methods known per se by adding additives such as lubricants,disintegrators, binders, excipients, etc. to the above-mentionedcompounds (1), (1') or their pharmaceutically acceptable salts. They maybe formed into oral or parenteral preparations such as tablets,capsules, powders, granules, liquids, suspensions, emulsions,suppositories, etc.

The dose of the compounds (1), (1') or pharmaceutically acceptable saltsof (1) or (1') varies depending on the administration route, conditionof the patient, etc. In general, it may be from 100 to 2000 mg/day, andespecially preferably from 200 to 1000 mg/day for adults in the case oforal administration.

The compounds (1), (1') or the pharmaceutically acceptable salts of (1)or (1') are administered to patients in need of PTCA due to ischemicheart diseases such as angina pectoris. Generally, administration of thecompounds starts about three days prior to the operation of PTCA, andcontinues over a period of three months after the operation. The periodin which the compounds are administered after operation may varyaccording to the condition of the location of the treated part.

EXAMPLE

The present invention will be explained in more detail by the followingexamples, which, however, should not be construed as limiting thepresent invention thereto. Test Example:

29 patients suffering from angina pectoris who received elective PTCA(43 sites ) orally took 2-phenyl-1,2-benzoisoselenazol-3(2H )-one(hereinafter referred to as compound A) after meal with a daily dose of200 mg, twice a day, 100 mg for each time, starting from three daysprior to the PTCA operation over 3 months after operation (treated group). Coronary angiography was performed before, immediately after and 3months after PTCA. The stenosed degree was measured byvideo-densitometry (Reiber JHC et al., Circulation 1985; 71:280-288),and inhibition of restenosis was evaluated on the basis of the findings.The results are shown in Table 2.

As control, placebo was given to 50 patients suffering from anginapectoris who received elective PTCA (84 sites) in place of compound A,and coronary angiography was performed before, immediately after and 3months after PTCA.

In both of the treated and control groups, calcium antagonists such asnifedipine and diltiazem, and antiarteriosclerotic agents such aselastase were concurrently administered as required. As a result, therewas no significant difference according to the χ² test between the twogroups with regard to the use of concomitant compounds and other patientcharacteristics including the age, the site of the lesion, etc.Accordingly, it is clear that the effect of inhibiting restenosisdemonstrated by the group treated with compound A is neither attributedto the sole use of these co-dosed drugs nor to the concomitant therapyby the use of these drugs and compound A.

                  TABLE 2                                                         ______________________________________                                        Time-dependent variation of stenosed degree                                   of post PTCA vessels                                                          Stenosed Degree                                                               Number of     Before    After                                                 sites (n)     PTCA      PTCA      3 Months                                    ______________________________________                                        Control 84        87 +/- 11 32 +/- 23                                                                             78 +/- 39                                 Group                                                                         Treated 43        89 +/- 10 35 +/- 28                                                                              54 +/- 31*                               Group                                                                         ______________________________________                                         (*P<0.05 vs Placebo) Chi square analysis                                 

As apparent from the results in Table 2, the group to which compound Awas administered showed a remarkable inhibition of restenosis in thelocation of operation when compared to the control group. At the pointof 6 months after operation, the onset rate of restenosis was 38.2% inthe control group while it was 18.6% in the treated group based on thenumber of patients. Accordingly, the treated group was clinicallyconfirmed to exhibit a higher restenosis inhibitory effect after PTCAthan the control group in either evaluation based on the number oflesion sites or that of patients.

Example 1

Tablets:

Tablets each having the following composition were prepared by a methodknown per se.

    ______________________________________                                        Compound A         50         mg                                              Carboxymethylcellulose                                                                           25         mg                                              Starch             5          mg                                              Crystalline Cellulose                                                                            40         mg                                              Magnesium stearate 2          mg                                              Total              122        mg                                              ______________________________________                                    

Industrial Applicability:

The compounds (1), (1') or pharmaceutically acceptable salts of (1) and(1') exhibit excellent inhibitory effect against restenosis after PTCAand less toxicity. Therefore, pharmaceutical agents containing these asactive ingredients are useful as an inhibitor for restenosis after PTCA.

We claim:
 1. An inhibitor for restenosis after percutaneous coronaryarterioplasty, which comprises, as an active ingredient, a compound ofthe following formula (1), (1') or a pharmaceutically acceptable saltthereof: ##STR6## wherein R¹ and R² are independently a hydrogen atom, ahalogen atom, a trifluoromethyl group, a nitro group, a C1-C6 alkylgroup or a C1-C6 alkoxyl group, and R¹ and R² may be linked to form amethylenedioxy group; R³ is an optionally substituted aryl group, anoptionally substituted aromatic heterocyclic group, an optionallysubstituted 5 to 7-membered cycloalkyl or cycloalkenyl group; R⁴ is ahydrogen atom, a hydroxyl group, an -S-glutathione residue, an-S-α-amino acid residue, or an aralkyl group optionally havingsubstituent(s) in the aryl moiety; and R⁵ is a hydrogen atom or a C1-C6alkyl group; Y is an oxygen atom or a sulfur atom; n is an integer offrom 0 to 5, and the selenium atom may be oxidized.
 2. A method ofinhibiting restenosis after percutaneous coronary arterioplasty, whichcomprises:administering a therapeutically effective amount of a compoundof the formula (1), (1') or a pharmaceutically acceptable salt thereof;##STR7## wherein R¹ and R² are independently a hydrogen atom, a halogenatom, a trifluoromethyl group, a nitro group, a C₁ 14 C₆ alkyl group ora C₁ 14 C₆ alkoxyl group, and R¹ and R² may be linked to form amethylenedioxy group; R³ is an optionally substituted aryl group, anoptionally substituted aromatic heterocyclic group, an optionallysubstituted 5 to 7-membered cycloalkyl or cycloalkenyl group; R⁴ is ahydrogen atom, a hydroxyl group, an -S-glutathione residue, an-S-α-amino acid residue, or an aralkyl group optionally havingsubstituent(s) in the aryl moiety; R⁵ is a hydrogen atom or a C₁ -C₆alkyl group; and R⁴ and R⁵ may be linked to form a single bond; Y is anoxygen atom or a sulfur atom; n is an integer of from 0 to 5, and theselenium atom may be oxidized.